Computational Modeling of NLRP3 Identifies Enhanced ATP Binding and Multimerization in Cryopyrin-Associated Periodic Syndromes.
Computational Modeling of NLRP3 Identifies Enhanced ATP Binding and Multimerization in Cryopyrin-Associated Periodic Syndromes.
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DOI：
10.3389/fimmu.2020.584364
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发表时间：
2020
影响因子：
7.3
通讯作者：
Fujita M
中科院分区：
文献类型：
--
作者：
Samson JM;Ravindran Menon D;Vaddi PK;Kalani Williams N;Domenico J;Zhai Z;Backos DS;Fujita M
Cyropyrin 相关周期性综合征 (CAPS) 是临床上独特的综合征，涵盖一系列表型谱，但却是由同一基因 NLRP3 的改变引起的。许多 CAPS 病例和其他 NLRP3 自身炎症性疾病 (NLRP3-AID) 直接归因于 NLRP3 中蛋白质编码的改变以及随后 NLRP3 炎症小体的失调，导致 IL-1β 介导的炎症状态。在这里，我们使用生物信息学工具、计算模型和计算评估来探索 NLRP3 突变的蛋白质组后果，这可能导致 NLRP3 炎症小体失调。我们分析了源自家族性寒冷自身炎症综合征 (FCAS)、Muckle-Wells 综合征 (MWS) 和非遗传性慢性婴儿神经皮肤和关节综合征（也称为新生儿发病多系统炎症性疾病 (CINCA/NOMID)）以及其他 NLRP3-AID 的 177 个突变。我们发现临床严重程度与 NLRP3 突变导致的预测结构变化的严重程度之间存在反比关系。生物信息学工具和计算模型显示，预计在结构上严重破坏的NLRP3突变位于ATP结合袋周围，并且ATP结合袋的特定蛋白质结构变化通过改变氢键和电荷相互作用导致ATP结合亲和力增强。此外，我们证明，预计在结构上轻度或中度破坏的NLRP3突变会影响蛋白质-蛋白质相互作用，例如NLRP3-ASC结合和NLRP3-NLRP3多聚化，从而增强炎症体形成和复合物稳定性。综上所述，我们提供的证据表明蛋白质结构机制可以解释 NLRP3-AID 中炎症小体激活的多种机制。
Cyropyrin-associated periodic syndromes (CAPS) are clinically distinct syndromes that encompass a phenotypic spectrum yet are caused by alterations in the same gene, NLRP3. Many CAPS cases and other NLRP3-autoinflammatory diseases (NLRP3-AIDs) are directly attributed to protein-coding alterations in NLRP3 and the subsequent dysregulation of the NLRP3 inflammasome leading to IL-1β-mediated inflammatory states. Here, we used bioinformatics tools, computational modeling, and computational assessments to explore the proteomic consequences of NLRP3 mutations, which potentially drive NLRP3 inflammasome dysregulation. We analyzed 177 mutations derived from familial cold autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome (MWS), and the non-hereditary chronic infantile neurologic cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease (CINCA/NOMID), as well as other NLRP3-AIDs. We found an inverse relationship between clinical severity and the severity of predicted structure changes resulting from mutations in NLRP3. Bioinformatics tools and computational modeling revealed that NLRP3 mutations that are predicted to be structurally severely-disruptive localize around the ATP binding pocket and that specific proteo-structural changes to the ATP binding pocket lead to enhanced ATP binding affinity by altering hydrogen-bond and charge interactions. Furthermore, we demonstrated that NLRP3 mutations that are predicted to be structurally mildly- or moderately-disruptive affect protein-protein interactions, such as NLRP3-ASC binding and NLRP3-NLRP3 multimerization, enhancing inflammasome formation and complex stability. Taken together, we provide evidence that proteo-structural mechanisms can explain multiple mechanisms of inflammasome activation in NLRP3-AID.
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DOI：
10.4049/jimmunol.0802367
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bryan NB;Dorfleutner A;Rojanasakul Y;Stehlik C
通讯作者：
Stehlik C
影响因子：
3.4
作者：
Awad, Fawaz;Assrawi, Eman;Amselem, Serge
通讯作者：
Amselem, Serge
影响因子：
13.3
作者：
Chang, Zenas;Spong, Catherine Y.;Stratton, Pamela
通讯作者：
Stratton, Pamela
影响因子：
5.8
作者：
Choi, Yongwook;Chan, Agnes P.
通讯作者：
Chan, Agnes P.
影响因子：
14.8
作者：
Coll, Rebecca C.;Hill, James R.;Schroder, Kate
通讯作者：
Schroder, Kate